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• D-form peptide hydrogel (Nap-DFDFKGRGD) can serve as scaffold for MSCs. • The RGD-containing hydrogel can enhance the proangiogenic activity of MSCs. • D-form amino acids increase biostability and half-life of this hydrogel. • RGD motif and D-form peptide hydrogel provide a promising option for MSC delivery. Mesenchymal stem cell (MSC)-based therapy was an ideal strategy for therapeutic angiogenesis in ischemic tissues. However, limitations such as heterogeneous proangiogenic nature and low cell survival following transplantation is a key challenge for clinical applications. Biofunctional materials such as extracellular matrix (ECM) and hydrogels are considered with great promise for improved therapeutics by constructing a supportable 3D microenvironment niche for transplanted cells. Here, we employ the RGD (Arg-Gly-Asp)-modified self-assembling D-form peptide hydrogel (Nap-DFDFKGRGD) to serve as the co-transplantation platform for human placental MSCs (hP-MSCs). Our data showed that this D-form hydrogel possessed excellent biocompatibility and biostability, exerting an anti-apoptosis capacity and improved cell viability in vitro. Furthermore, we found that the self-assembled hydrogel improved cell survival, as well as promoted collateral vessel revascularization by bioluminescence imaging (BLI) and micro-CT imaging analysis. Further study confirmed significant up-regulation of proangiogenic cytokines of hP-MSCs in vivo. These results demonstrated the improvements of therapeutic efficacy of hP-MSCs in terms of tissue regeneration and functional recovery in the murine hindlimb ischemia (HLI) model. In conclusion, the strategy provided a promising option for ischemia diseases by improving the proangiogenic effects of MSCs and further for enhancing the therapeutic efficiency of MSCs with the RGD motif and the D-form peptide hydrogel. [ABSTRACT FROM AUTHOR]